Streptococcus pyogenes, the group A streptococcus (GAS) is an important human pathogen causing frequent self-limiting diseases that may lead to serious sequelae. In addition, the GAS seems to be [unreadable]re-emerging[unreadable] as an important pathogen that causes life-threatening invasive disease. The current spread of antibiotic resistance among GAS strains in this country makes development of alternative interventions to treat and prevent infections of this organism a very high priority. We will continue to use molecular genetic and biochemical approaches to obtain a better understanding of regulation of the virulence factors of this organism. This proposal focuses on the global regulator, CovR/S. We will elucidate the role of the CovR/S two component signal transduction system in response to environmental changes like those encountered in the host during disease development (Aim 1) and the interaction of CovR/S with other members of the transcriptional regulatory network in GAS (Aims 2,3,4). The results of these investigations will provide a better understanding of the molecular aspects of GAS pathogenesis and its interaction with its human host. This will suggest new targets for development of therapeutic interventions to prevent and/or ameliorate the many types of GAS diseases.